In order to account for the remarkable catalytic power of enzymes, it is generally considered that the activation free energy is contributed both by binding of the substrate to the enzyme (step 1) and by chemical manipulation of the bound substrate (bond-making and breaking, step 2). Popular opinion holds that most of the activation energy is supplied in step 2. We have proposed, however, that the overall catalytic process can be explained more reasonably if it is assumed that the first step (binding) contributes a more significant, and sometimes major, share of the activation energy. To support this theory, we have synthesized a large variety of test-tube models which simulate the bound substrate by being frozen into a single, favorable conformation and by having the interacting groups brought into the closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions at rates comparable to those catalyzed by enzymes, sometimes even too fast to measure. The protein raises both the entropic and enthalpic components of the substrate by binding it in a single, rigid conformation. Our original theory proposed that the principal sources of free energy increase during binding were conformational freezing, desolvation, electronic deformation, etc. Our new studies with tryptophan analogs have provided yet another factor which we had not considered originally: in those cases in which a substrate is capable of tautomeric equilibrium, the enzyme may be able to stabilize (by binding alone) the thermodynamically unfavorable tautomer (Tenutautomer). This simple event would necessarily increase the free energy content of the bound substrate and serve as "activation." We have already proven the reality of this phenomenon for tryptophan by demonstrating the potent inhibitory and stereospecific properties of TENUTAUTOMER ANALOGS. We are presently involved in the design, synthesis and testing of other stable tenutautomer analogs.